The phosphatidylinositol-3-kinase (PI3K) signaling pathway is important for the growth and survival of cancer cells in many different types of human malignancy. See, Granville C A et al, “Handicapping the Race to Develop Inhibitors of the Phosphoinositide 4-Kinase/Akt/Mammalian Target of Rapamycin Pathway,” Clin Cancer Res, 2006; 12(3) 679-89. This pathway receives upstream input from ligand-receptor interactions, such as the epidermal growth factor receptor and insulin-like growth factor receptor, and signals through downstream effectors, such as the mammalian target of rapamycin (mTOR). mTOR is a critical downstream effector molecule that regulates the production of proteins critical for cell cycle progression and many other important cellular growth processes. See, Abraham R T and Gibbons, J J, “The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res, 2007; 13(11) 3109-14.
Dysregulation of the PI3 kinase axis is common in human cancer due to overactive growth factor receptor signaling, activating mutations of PI3K, loss of function of the PTEN tumor suppressor, and several other mechanisms that result in activation of mTOR kinase activity. Clinically, successful pharmacological inhibition of the PI3K axis has focused on the upstream growth factor receptors and the downstream effectors of PI3 kinase, such as mTOR. There is now substantial clinical evidence showing that mTOR inhibitors can provide clinical benefit to patients with advanced malignancies.
Insulin-like growth factor receptor 1 (IGF-1R), a tyrosine kinase receptor of the insulin receptor family, is involved in cell proliferation, differentiation, and plays an important role in the transformation and maintenance of malignant cells in many types of cancer. See, Baserga, R, et al., “Mini Review: The IGF-1R receptor in cancer biology,” hit. J. Cancer 2003; 107: 873-77. IGR-1R and its ligand IGF-2 are over expressed in many types of advanced cancer, and ligand-stimulated receptor signaling promotes the proliferation of cancer cells in vitro. Significantly, IGF-1R signaling is closely linked to the PI3K axis. IGF-1R inhibition has shown potent anti-cancer effects in preclinical studies, and a number of IGF-1R inhibitors are currently in clinical development.
The combination of mTOR and IGF-1R inhibitors may provide a synergistic effect by inhibiting both upstream and downstream molecular targets in the PI3K axis. The inhibition of mTOR can lead to the activation of a feedback loop that activates the Akt oncogene, which manifests as increased levels of phospho-Akt in tumor cells in vitro and from tumor biopsies taken from patients treated with mTOR inhibitors. See, Sun, S—Y et al., “Priority Report: Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition,” Cancer Res 2005; 65(16): 7052-58, and Gardner, H et al., “Biomarker analysis of a phase II double-blind randomized trial of daily oral RAD001 (everolimus) plus letrozole or placebo plus letrozole as neoadjuvant therapy for patients with estrogen receptor positive breast cancer,” San Antonio Breast Cancer Symposium. San Antonio, Tex., Dec. 13-16, 2007. Abstract 2006. This feedback loop can involve signaling through IGF-1R and the insulin receptor substrate, and is inhibited by IGF-1R inhibitors. As a result, preclinical studies have shown that the combination of IGF-1R inhibitors and mTOR inhibitors leads to additive or synergistic anti-tumor activity in vitro. Recently, two groups have independently reported the results of combining rapamycin with anti-IGF-1R antibodies in xenograft models of human sarcomas. See, Kurmasheva R T, et al., Poster: “Combination of CP-751871, a human monoclonal antibody against the IGF-1 receptor with rapamycin results in highly effective therapy for xenografts derived from childhood sarcomas,” EORTC 2007, and Darko, I A et al., Abstract: “Evaluation of combined insulin-like growth factor receptor type I (IGF-1R) and mTOR pathway blockade in sarcoma xenograft models. AACR Annual Meeting 2007, 4760. In one of these studies, complete regressions of established Ewing's and osteosarcoma xenografts were observed while in the other potent anti-tumor activity with at least additive benefits from the combination was observed.